HEART-FID confirms IV iron safety for HF but falls short in efficacy

The HEART-FID trial narrowly missed its primary endpoint, showing modest improvement in all-cause mortality, heart failure hospitalizations (hHF), and exercise function with ferric carboxymaltose (FCM) in HFrEF* patients with iron deficiency (ID).

“Despite suggesting potential benefits, our trial did not meet its primary efficacy endpoint,” said Dr Robert Mentz from the Duke Clinical Research Institute, Durham, North Carolina, US, at ESC 2023. “[However,] it did confirm the safety of IV FCM.”

For the primary hierarchical endpoint, modest numerical differences were observed between the FCM and placebo arms in terms of all-cause death (8.6 percent vs 10.3 percent) and total hHF at 12 months (13.3 percent vs 14.8 percent), and 6-minute walk distance (6MWD) at 6 months (mean change, +8 vs +4 metres). [ESC 2023, Hot Line 2 session]

These differences translated to an absolute risk reduction of 1.7 percent for all-cause death, 270 fewer hHF days, and a 4-metre benefit in 6MWD with FCM. The p value of 0.019 did not meet the prespecified significance level of 0.01 based on a higher US regulatory threshold, noted Mentz.

Overall win ratio with FCM vs placebo was 1.10. While this implied 10 percent more ‘wins’ with FCM, it still did not meet the prespecified significance level.

For the top secondary endpoint of time to first hHF or cardiovascular (CV) death, fewer events were reported with FCM vs placebo (31.0 percent vs 32.2 percent; hazard ratio [HR], 0.93). A similar trend was observed for time to CV death (16.4 percent vs 17.9 percent; HR, 0.86).

On prespecified responder analyses for change in 6MWD, there was a ≥24-percent increase in the likelihood of response with FCM vs placebo.

There were similar rates of treatment-emergent adverse events between the FCM and placebo arms (27.0 percent vs 26.2 percent).

The hypophosphatemia case in the FCM arm resolved. Of the two angioedema cases reported with FCM, one was potentially related to the study drug. “This was a case of facial oedema of moderate severity, but this resolved within hours following oral therapy,” said Mentz.

Five cases of hypersensitivity were reported with FCM (three potentially drug-related). One was classified as severe, but all patients were recovering, nonetheless.

 

ID tied to worse symptoms, prognosis

“ID is common in HFrEF patients and is associated with worse symptoms and adverse prognosis,” said Mentz. “ID without anaemia is associated with worse NYHA** class and reduced survival,” echoed discussant Professor Scott Solomon from Harvard Medical School, Boston, Massachusetts, US.

About 3,000 patients (mean age 69 years, 34 percent female) with chronic HFrEF with ID*** were randomized 1:1 to receive FCM or placebo on top of background therapy. Patients <50 kg received two 15-mg/kg FCM doses, while those ≥50 kg were given two 750-mg doses. By month 6, 82 percent of FCM recipients transitioned to placebo due to adequate iron repletion. Cumulative mean FCM dose during year 1 was 1,809 mg. Median follow-up was 1.9 years.

 

Pooled analysis suggests benefit

While the study ‘technically’ did not meet the primary endpoint, it did underpin the modest biologic benefit of IV FCM for HFrEF patients with ID, Solomon said.

“The observed differences in the primary endpoint were driven by the wins in death, but the other components contributed to a larger proportion of decisions in the analysis,” said Mentz. “The totality of evidence with IV FCM from prior studies assessing symptomatic and functional status endpoints, combined with clinical outcome studies including HEART-FID, show the overall safety and clinical benefits of IV FCM in HFrEF with ID.”

Of note as well were the results of an analysis that pooled the HEART-FID findings with that of two other studies. In this meta-analysis presented during the same ESC Hot Line session, the reductions in total CV hospitalizations and CV death with FCM vs placebo were significant (rate ratio [RR], 0.86; p=0.029). FCM also reduced total CV hospitalizations (RR, 0.83; p=0.009) and total hHF (RR, 0.84; p=0.025). Albeit nonsignificant, a trend towards a reduction in the composite of total hHF and CV death was observed (RR, 0.87; p=0.076).

 

Positive in ‘another universe’

Solomon commented that the HEART-FID study “might have been positive in ‘another universe’, [as] all components went in the same direction.”

“The modest overall benefit, especially for the ‘hard’ outcomes we care most about in HF, and high discontinuation rate, will need to be considered, along with the totality of evidence from several IV iron trials in HF to inform clinicians regarding the use of IV iron as adjunct therapy in appropriate HF patients,” Solomon added.